Throughout this application, various references are referred to within parenthesis. Disclosures of these publications in their entireties are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains.
This invention relates to a process for preparing a chemical substance. 6-Methyl-3,4-dihydro-1,2,3-Oxathiazin-4-one dioxide is the compound expressing as the following molecular formula (hereinafter Acesulfame) 
Because of the acidic hydrogen on the nitrogen atom, the compound is able to form salts (with bases). The non-toxic salts, for example the sodium, Na, potassium, K and calcium, Ca salt, can, because of their sweet taste, be used as sweeteners in the foodstuffs sector, the K salt (xe2x80x9cAcesulfame Kxe2x80x9d) being of particular importance.
Acesulfame-K (AK) is a kind of synthesized high-degree and healthier sweetener. It tastes like cane sugar but 200 times sweeter than the latter. Because of the remarkable characters, such as strong sweet, good stability, fresh taste, fine flavor, no bitter metallic and chemical feeling, cheaper price, safety and no side effect after a large number of toxic tests, AK is a favorite in the international market. Since 1980xe2x80x2s, in many developed countries such as America and Europe, Ak. has widely been used in the production of foods, medicine and cosmetics. These years, with AK more widely being used in beverage and medicine, AK is widely accepted by more and more clients as an important new kind of healthier sweetener.
A number of different processes are known for the preparation of AK and its non-toxic salts. Forty-five patents of Acesulfame filed in five countries were reviewed.
See the following list.
The description of the processes for preparing Acesulfame in these patents may be summarized below:
(1) Using fluoro or chlorosulfonyl isocyanate (XSO2NCO with x=Cl or F) reacted with tertiary-butylacetoacetate. In the processes, the intermediate fluoro or chlorosulfonyl isocyanate was produced necessarily to use potassium cyanate, that is a very poisonous substance. It is very easy to cause a person working at the post to be seriously hurt, or even death if the safety measures were not perfectly observed. Therefore, this process is not suitable for large industrial production. Additionally, this reaction needs to carry out at lower temperature, thus it is necessary to take much energy that making the productive costs increase. As mentioned above, the process is disuse in industry at present.
(2) Reactions of sulfurylfluoride and acetoacetamide.
(3) Reactions of diketene and sulfamoyl fluoride (H2NSO2F). In methods (2) and (3) it is difficult to produce sulfurylfluoride and sulfamoyl fluoride in industry. It is necessary to use hydrofluoride for producing the above two substances. A common work lacks perfect safe guard to protect workers against the health hazard of HF. Therefore the above two methods aren""t suitable to produce Acesulfame in industry.
(4) The reaction of ring closure of acetoacetamide-N-sulfonic acid with sulfur trioxide at lower temperature was applied to prepare Acesulfame.
xe2x80x83But in this process the quantity of sulfur trioxide is as much as four to five times of acetoacetamide-N-sulfonic acid while produced 1 ton of Acesulfame therefore 2 tons of waste sulfuric acid was given here, it was very difficult for manufacturers to treat so large amount of waste acid. The reaction of ring closure must be carried out at lower temperature so it needs to take a lot of energy to reduce the temp of reactants. Additionally, sulfur trioxide is very easy to polymerize turning into various forms of Polymers. At room temperature these polymers are in solid form. Thus the concentration of Sulfur trioxide is difficult to control during the period of practical operation. As a result it leads to the unsteady yield of products desired. Sulfurtrioxide is also a strong oxidant as it absorbed water to turn into sulfuric acid which has strong corrosive action to iron or steel equipments. Judging from this the process isn""t a good way for preparing Acesulfame.
In CN patent No.1092066 the synthetic methods of Acesulfame are shown in the following reaction equations: 
In the above equation (2) sodium azide was used to react with p-chlorophenoxide sulfonylchloride for preparing p-chlorophenoxide sulfonylazide. After completion of the reaction, solvent was required to distill off, but at this moment attention must be paid to the temperature of distillation. If the distilling temperature exceeded 25xc2x0 C., it was surely to lead to a terrible explosion. It is a dangerous factor that exists in this synthetic process.
In the above equation (3) p-chlorophenoxide sulfonylazide was reduced to amino-group with sodium tetrahydroborate (NaBH4), but this reductive agent sparingly dissolves in tetrahydrofuran. Under this condition the reductive time, was very long that caused the reductive effect bad, therefore it made the yield of the product unsteady according to the above mention in CN patent 1092066. The two defects of the synthetic processes of Acesulfame must be modified to the reaction equations (2) and (3). Therefore, we have done many experiments in order to find a good way to replace the above reaction equations (2) and (3).
This object has been achieved according to the invention by a modification of the process of China patent publication No.1092066.
Our group found an advertisement in a German Journal in which Acesulfame-K was described in 1983. In 1992, our group had synthesized Acesulfame-K. The result led to filing a patent application in China in 1992.
However, the above synthetic method of Acesulfame-K was not satisfactory. Below describes an improved method for Acesulfame-K.
Acesulfame-K""s patents:
Some main differences in preparing Acesulfame-K between German, US patents and our invention are:
Synthetic schemes are different:
1 USP, DE: 
2 Our Invention: 
B, Raw materials used as synthetic components are different between USP, DE patent and Our Invention:
In USP: 
These substances must be manufactured by producer. One can""t easily obtain them from market. If one needs to produce (b), (c), NaCN, HF, two poisonous substances must be used in producing processes. 
In Our invention:
These substances are very easy to be bought from market.
C, The waste substances occurred in our synthetic ways are less than that of US patent in preparing Acesulfame-K.
In our invention:
All solvents can be recovered from each step, and be reused in precedent steps. By product, Potassium Chlorophenoxide can be easily separated from Acesulfame-k and be reused in the first step.
In US Patent:
The waste substances produced in synthetic Acesulfame-k are more than ours. Such as SO3+H2Oxe2x86x92H2SO4 in U.S. Pat. Nos. 5,011,982 and 5,103,046, those amounts are large, and can""t be reusable. Because it contained a lot of impurities and its color is dark brown. So it becomes a big problem to process for producers.
This invention provides a method for preparing Acesulfame comprising steps of: (a) using the substituted sodium phenoxide or the substituted phenol reacted with sulfonyl chloride in a suitable inert solvent under catalysis to produce substituted phenoxide sulfonylchloride, Compound I; (b) reacting Compound I with ammonia under catalysts to produce substituted phenoxide sulfonyl-amide, Compound II; (c) reacting Compound II with diketene in an organic solvent under amine catalysts to produce acetoacetamide-N-sulfonyl-substituted phenoxide, Compound III; (d) dissolving Compound III in lower alcohol and addition of alkali metal hydroxide or carbonate so that cyclyzation of Compound III will occur to produce acesulfame; and (e) harvesting the produced Acesulfame.
This invention provides a method for preparing Acesulfame comprising steps of (a) using the substituted sodium phenoxide or the substituted phenol reacted with sulfonyl chloride in a suitable inert advent under catalysis to produce substituted phenoxide sulfonylchloride, Compound I; (b) reacting Compound I with ammonia under catalysts to produce substituted phenoxide sulfonyl-amide, Compound II, (c) reacting Compound II with diketene in an organic solvent under amine catalyses to produce acetoacetamide-N-sulfonyl-substituted phenoxide. Compound III; (d) dissolving Compound III in lower alcohol and addition of alkali metal hydroxide or carbonate so that cyclization of Compound III will occur to produce acesulfame; and (e) harvesting the produced Acesulfame.
In an embodiment of step (a) the inert solvent includes a group of alkyaryl hydrocarbons, halohydrocarbons.
In a further embodiment, the reaction comprises some cosolvents.
In another embodiment of step (a), the solvent includes but is not limited to methylene chloride, 1,1-dichloro ethane, and 1,2-dichloro ethane.
In a separate embodiment, the catalysts of step (a) includes alkyl of alkoxy ammoniumhalides.
In another embodiment of step (a) the temperature is at approximately xe2x88x9210 to +20xc2x0 C.,
In another embodiment of step (a), the reaction is stirring continuously.
In a separate embodiment of step (a), the pressure of reaction inside the column is between 2 to 10 Mpa.
The catalysts include but are not limited to following compounds: SiO2xe2x80x94Al2O3, NiO, Cu2O, TiO2, ThO2 and Cu(OH)NH4CrOH, NI6Al2C(OH)16CO3-4H2O, Ni/Al2O3xe2x80x94NiO/SiO2, or other metals including: pd, pt, Ni.
In an embodiment of step (C), organic solvent includes benzenes, halohydrocarbon, ether, tetrahydrofuran, and acetonitrile.
In a separate embodiment of step (c), the temperature is approximately xe2x88x925xc2x0 C. to +10xc2x0 C.
The amine catalysts of step (c) included but are not limited to trimethylamine triethylamine, tri-n-propylamine, triisopropylamine, tri-n-butylamine, and triethylamine.
In an embodiment of step (a) and step (b), solvents used include the following organic solvent: benzene, methylenechloride, monochloromethane, chloroform, ethylidene chloride, 1,2-dichloroethane, tetrahydrofurane toluene, and o-,m-,p-three kinds of xylene.
This invention encompasses the substituted radical R in its molecular formula, represented Hxe2x80x94, 2-CH3xe2x80x94, 2,6-di-CH3xe2x80x94, 2-Cl, 4-Cl, 2-NH2xe2x80x94, catalyst used here was selected from a group consisting of alkyl-or alkoxy-onium salts, tribenzyl ethyl ammoniumchloride, tribenzyl ammonium bromide, tetra-n-butylammonium bromide, tetra-1-butyl ammonium chloride and tetra-1-butylammonium bromide.
In an embodiment of step (c), the solvent includes the following solvent: benzene, methylenechloride, monochloromethane, chloroform, carbontetrachloride, ethylchloride, ethylidenechloride, dichloroethane, diethylether, methyl ethyl ether and tetrahydrofuran. The amine catalysts are tertiary amines in which each N atom has up to 20, or only up to 10 carbon atoms selected as catalyst. In a further embodiment, the amines catalysts is trimethylamine, triethylamine, tri-n-propylamine, triisopropylamine, tri-n-butylamine, triisobutylamine, N,N-dimethylamine etc. A particular preferred is the triethylamine. The reaction time can vary within wide limits in general, i.e. between 1.5 to 12 hours, Compound III can be recrystallized from a suitable solvent such as acetone, methylacetate or ethanol.
In an embodiment of step (d), the hydroxide or carbonate of alkali metals is selected from NaOH, KOH, Na2CO3, K2CO3, K alcoholate, ROK where R=CH3xe2x80x94, CH3CH2xe2x80x94, CH3CH2CH2xe2x80x94.
In a separate embodiment of step (d), the alcoholic solvent is a lower alkylalcohol. In a further embodiment, the alcohol solvent is methanol, ethanol and propanol.
In a still further embodiment of step (d), the temperature in the reaction of ring closure at approximately 10xc2x0 C. to 30xc2x0 C. In another embodiment of step (d), the pH value at the end of the ring closure reaction was 8 to 12.
This invention also provides acesulfame produced by the above method and compositions comprising the produced acesulfame. Acesulfame-K, an intense sweetener being wide used in food and beverage now, may be prepared by: a) using the substituted sodium phenoxide or substituted phenol as the starting substance synthesized the following three intermediates; The substituted phenoxide sulfonylchloride(I), The substituted phenoxide sulfonylamide(II), The acetoacetamide-N-sulfonyl-substituted phenoxide(III); b) particularly, the (II) was prepared by using the liquid or gaseous ammonia to react with (I) under the action of some catalysts in a reaction column. The (III) was prepared by using the (II) to react with diketene; c) Acesulfame-K was prepared by ring-closure in the molecule of (III) with methanol solution of KOH or K2CO3.
Thus, the invention relates to a process for the preparation of Acesulfame and its non-toxic salts is described as follows:
Step (1) Preparing the substituted phenoxide sulfonylchloride [hereafter called Compound I].
Using the substituted sodium phenoxide or the substituted phenol that reacted with sulfonyl chloride, under the catalytic action to produce Compound (I). The reaction temperature was at xe2x88x9210xc2x0 C. to approximately xe2x88x9220xc2x0 C.
Alkyl-or alkoxyammonium halide was used as catalyst.
Their reaction was carried out in the solvent of chlorohydrocarbon, alkyl-arylhydrocarbon, if necessary, added some cosolvent to above solvents for raising their solubility, such as polyethyleneglycol (PEG) is normally used, the molecule weight of PEG was selected between 400 to 600.
Step (2) preparing the substituted phenoxide sulfonylamide [hereafter called Compound II]
Let the Compound I dissolved in halohydrocarbon solvent, and then being pumped the solution into the reaction column. Cooling the solution inside the column to the temperature at xe2x88x925xc2x0 C.xcx9c+30xc2x0 C. The pressure in the column was nearly regulated in 2xcx9c10 Mpa by sending liquid or gaseous ammonia into the column for going on the ammonification reaction with Compound I. Under the actions of some catalysts which had been put into the column before the process begun. After the reaction, obtained the intermediate, Compound II.
Step (3) Preparing acetoacetamide-N-sulfonyl substituted phenoxide [hereafter called Compound III].
Using the above Compound II reacted with diketene in a suitable inert organic solvent in which appropriate amount of a tertiary amine was used as catalyst to produce Compound III.
An inert organic solvent used here was selected from the following organic solvents, such as benzene, halogenated aliphatic hydrocarbons, preferably those having up to 4 carbon atoms, for example, methylene chloride, chloroform, 1,2-dichloroethane, trichloroethylene, tetrachloroethylene, aliphatic ethers, such as furamidine, dioxane etc. aliphatic nitrites, preferably acetontrile. The reaction temperature was at xe2x88x925xc2x0 C.xcx9c+5xc2x0 C.
Step (4) Preparing Acesulfame-K.
At room temperature let the Compound III dissolve in the lower alcohol. Under continuously stirring, the alcoholic solution of alkali metal hydroxide or carbonate van adding dropwise to the alcoholic solution of Compound III. Under this condition the Compound III occurred a cyclization reaction in its molecule and the final Compound. Acesulfame-K, was precipitated from the alcoholic solution; at PR 8-12.
In step (1) the substituted R in the molecule of sodium Phenoxide or phenol may be H, -2xe2x80x94CH3-, 2,6-dimethyl-, 2-chloro-, 4-chloro, 2-amino.
Catalyst used in step (1) was selected from alkyl-or alkoxyloniumshalide such as benzyl triethylammoniumchloride, benzyl triethylammoniumbromide, tetra-n-butylammoniumbromide tetra-i-butylammoniumchloride. Suitable inert organic solvent used in step (1) was Selected from chlorohydrocarbon alkyl, arlhydrocarbon such as benzene, dichloromethane, chloroform, 1, 1-dichloroethane, 1,2-dichloroethane, 1,2-dichloroethane toluene, m-,o-,p-three kind, of xylene, if necessary added some cosolvents to anyone of the above solvents such as polyethyleneglycol (PEG M.W 400xcx9c600). etc.
In step (2) ammonia used here was liquid or gaseous state, catalysts used here were selected from the following substances. Hexamethyleneamine, SiO2xe2x80x94Al2O3, TiO2, ThO2, NiO/Al2O3, cuprous oxide, Cupric oxide, Cu(OH)2, NH4CrOH, Ni6Al2(OH) CO3.4H2O, Pd, Pt, Ni, Rh and the mixtures oxides of various metals.
Solvent used here was selected form benzene, methylenechloride, chloroform. 1,1-dichloroethane, 1,2-dichloroethane, toluene, Oxe2x80x94, m, p-three kinds of xylene, tetrahydrofuran etc.
In step (3) the solvent used here was selected from Benzene, monochloromethane, methylenechloride, chloroform, carbontetrachloride, monochloroethane, 1,2-dichloroethane, 1,1-dichloroethane, ether methylethylether, acetone, tetrahydrofuran, acetonitrile, etc.
Akylamine used here was selected from diethylamine triethylamine, tri-n-propylamine, triisopropylamine, tri-n-butylamine, tricyclohexylamine, N,N-dimethylaniline, benzyl dimethylamine, pyridine substituted pyridines. A particularly preferred amine is triethylamine.
In step (4) the hydroxide or carbonate of alkali metals used here was selected from NaOH, Na2CO3, KOH, K2CO3, preferably using a potassium base, for examples, KOH, K2CO3, K alcoholate etc.
Alcoholic solvent used in step (4) was selected from alkyl alcohol having 1xcx9c3 atoms of carbon such as methanol, ethanol, propanol etc. A particularly preferred alcohol is methanol.
The temperature for cyclization reaction was controlled at 10xc2x0 C.xcx9c30xc2x0 C., PH value was 8xcx9c12.
This invention improves the reaction in step (2) of CN patent, No.1092066. Liquid or gaseous ammonia was used instead of sodium azide. Under the action of some catalysts at a certain pressures and temperature the reaction would be taking place. Catalyst such as SiO2, Al2O3 or others was put into the reaction column, and then the methylene chloride solution of Compound I was pumped into the same column. Liquid ammonia was let to enter into the same column till it cooled at the temp 0xc2x0 C.xcx9c15xc2x0 C. The speed of liquid or gaseous ammonia was adjusted to allow the pressure meter fitted on the top of the column indicated 2-10 Mpa. The aminolysis reaction at this pressures and temperature was carrying on to 3 h. If the pressure dropped during the reaction period, at this moment the speed of liquid or gaseous ammonia entering the column should be adjusted till the pressure was steadily. After the reaction having proceeded for 3 h, sampling the reaction liquid to be tested. If the content of desired product reached 80xcx9c90%, It indicated that the reaction was completed.
Let the reaction solution flow into a distillatory, and under reduced pressure for distilling the residuce ammonia and methylene chloride, thus obtained p-chlorophenoxide sulfonylamide.
Some Advantages of this Invention are Summed up as Follows:
Technical process is simple, reaction time is short and the industrial wastes are treated easily. The yields of three intermediates and finished substance are higher than other methods. Therefore the defects in CN patent, 1092066(Application No.93102189) have been improved.